Sie sind auf Seite 1von 7

Received: 5 April 2021 Revised: 24 June 2021 Accepted: 28 June 2021

DOI: 10.1111/cge.14020

ORIGINAL ARTICLE

Tenorio syndrome: Description of 14 novel cases and review


of the clinical and molecular features

Jair Antonio Tenorio-Castaño1,2,3 | Pedro Arias1,2 | Alberto Fern


andez-Jaén4 |
Guillermo Lay-Son5 | Gloria Bueno-Lozano6 | Allan Bayat7 | Laurence Faivre3,8,9 |
Natalia Gallego1,2,3 | Sergio Ramos1,2 | Kameryn M. Butler10 | Chantal Morel11,12 |
Stasia Hadjiyannakis13 | James Lespinasse14 | Frederic Tran-Mau-Them15 |
Fernando Santos-Simarro1,3,16 | Lucile Pinson17 |
Antonio Federico Martínez-Monseny18,19 | María del Mar O'Callaghan Cord18 |

Sara Alvarez 20
| Elliot S. Stolerman10 | Camerun Washington10 |
Feliciano J. Ramos1,6,21 | The S. O. G. R. I. Consortium1,2 | Pablo Lapunzina1,2,3
1
n Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain
CIBERER, Centro de Investigacio
2
noma de Madrid
Overgrowth Syndromes Laboratory, INGEMM, Instituto de Genética Médica y Molecular, IdiPAZ, Hospital Universitario la Paz, Universidad Auto
(UAM), Madrid, Spain
3
Ithaca, European Reference Network, Brussels, Belgium
4
nsalud Madrid, Universidad Europea de Madrid, Spain
Hospital Universitario Quiro
5
n de Pediatría, Facultad de Medicina, Pontificia Universidad Cato
Unidad de Genética, Divisio lica de, Chile
6
n,
Unit of Clinical Genetics, Service of Paediatrics, School of Medicine, University Hospital 'Lozano Blesa, University of Zaragoza, CIBERER-GCV02 and ISS-Arago
Zaragoza, Spain
7
Department of Pediatrics, Hvidovre Hospital, University of Copenhagen, Denmark
8
Centre de Référence Anomalies du Développement et Syndromes Malformatifs, FHU TRANSLAD, Hôpital d'Enfants, CHU Dijon, Dijon, France
9
UMR1231 GAD, Inserm - Université Bourgogne-Franche Comté, Dijon, France
10
Cytogenetics Laboratory, Greenwood Genetic Center, Greenwood, South Carolina, USA
11
University Health Network, Fred A. Litwin Family Centre in Genetic Medicine, Toronto, Ontario, Canada
12
Department of Medicine, University of Toronto, Toronto, Ontario, Canada
13
Division of Endocrinology and Metabolism, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada
14
Service de Cytogenetique, Centre Hospitalier de Chambéry, Chambéry, France
15
UF6254 Innovation en Diagnostic Genomique des Maladies Rares Bat, Pôle de Biologie, CHU, Dijon, France
16
noma de Madrid (UAM),
Clinical Genetics section, INGEMM, Instituto de Genética Médica y Molecular, IdiPAZ, Hospital Universitario la Paz, Universidad Auto
Madrid, Spain
17
Départment de Génétique Médicale, Maladies Rares et Médecine Personnalisée, CHU de Montpellier, Montpellier, France
18
Clinical Genetics section, Department of Genetic and Molecular Medicine and Pediatric Institute of Rare Diseases (IPER), Hospital Sant Joan de Déu, Barcelona,
Spain
19
Department of Pediatric Neurology, Hospital Sant Joan de Déu, Barcelona, Spain
20
NIMGENETICS, Calle de Anabel Segura, Madrid, Spain
21
Unit of Pediatric Endocrinology, Service of Paediatrics, University Hospital Lozano Blesa, Zaragoza, Spain

Correspondence
Pablo Lapunzina, INGEMM-Instituto de Abstract
Genética Médica y Molecular, IdiPAZ- Instituto Tenorio syndrome (TNORS) (OMIM #616260) is a relatively recent disorder with very
n Sanitaria del Hospital
de Investigacio
Universitario La Paz, Universidad Autonoma few cases described so far. Clinical features included macrocephaly, intellectual

Clinical Genetics. 2021;1–7. wileyonlinelibrary.com/journal/cge © 2021 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd 1
2 TENORIO-CASTAÑO ET AL.

de Madrid (UAM), Paseo de la Castellana


261-28046, Madrid, Spain. disability, hypotonia, enlarged ventricles and autoimmune diseases. Molecular under-
Email: pablo.lapunzina@salud.madrid.org and
lying mechanism demonstrated missense variants and a large deletion encompassing
plapunzina@ciberer.es
RNF125, a gene that encodes for an U3 ubiquitin ligase protein. Since the initial
Funding information
description of the disorder in six patients from four families, several new patients
Federación Española de Enfermedades Raras
(FEDER), Grant/Award Number: PI20 were diagnosed, adding more evidence to the clinical spectrum. In this article, we
described 14 additional cases with deep phenotyping and make an overall review of
all the cases with pathogenic variants in RNF125. Not all patients presented with
overgrowth, but instead, most patients showed a common pattern of neu-
rodevelopmental disease, macrocephaly and/or large forehead. Segregation analysis
showed that, though the variant was inherited in some patients from an apparently
asymptomatic parent, deep phenotyping suggested a mild form of the disease in
some of them. The mechanism underlying the development of this disease is not well
understood yet and the report of further cases will help to a better understanding
and clinical characterization of the syndrome.

KEYWORDS
genomic medicine, macrocephaly, neurodevelopmental, overgrowth, ring-finger, RNF125,
Tenorio syndrome, ubiquitin ligase

1 | I N T RO DU CT I O N have an effect on the PI3K-AKT pathway, in which IPS-1 is


involved as well. The specific mechanism from which variants in
Clinical and molecular characterization of human genetic conditions RNF125 may lead to clinical features of the syndrome has not
is extremely useful not only to confirm the suspected clinical diag- been fully elucidated yet. PI3K-AKT represent one of the major
nosis, but also to perform an appropriate follow up and manage- pathways associated with OGS, many of which are caused by path-
ment of the affected patients and their families. Overgrowth ogenic activating variants in genes that encode proteins related to
disorders/syndromes (OGD/OGS) represent a heterogeneous group this pathway, that is, Proteus syndrome caused by AKT1,3 PIK3CA
of diseases, all of them characterized by an increase of head cir- Overgrowth Related Disorders or PROS4 and Smith-Kingsmore syn-
cumference, weight and/or height above 97th centile or +2 SD drome caused by pathogenic variants in MTOR.5 In many of these
1
above the mean. Most OGS includes additional findings, especially disorders and others caused by pathogenic variants in genes within
neurodevelopmental abnormalities, which are present in the major- the same pathway, similar clinical features were reported, including
ity of the affected patients. Thus, identification and deep clinical intellectual disability, autism spectrum disorder and seizures, among
characterization of patients with OGS represent a major challenge other.6–8
in daily clinical practice. Here, we described fourteen additional patients with RNF125
Tenorio syndrome (TNORS; MIM #616260) is one of the most variants. TNORS should be classified as a neurodevelopmental disor-
recently described OGS syndromes. In the original publication in der rather than an overgrowth syndrome, due to the relevant addi-
2014,2 we reported on six patients from families who had over- tional findings presented herein, which showed a variable degree of
growth, intellectual disability (mild to moderate), inflammatory dis- expression and incomplete penetrance. Our work provides an updated
orders, ventriculomegaly and hypoglycemia. The observation of clinical phenotype of patients with this syndrome, presents fourteen
overgrowth in the patients described in the original publication additional patients and discuss its molecular mechanism of
might be a selection bias because all patients came from the Span- inheritance.
ish Overgrowth Registry.2 In all of them–except for one patient
with a large deletion encompassing RNF125- a pathogenic missense
variant was/identified in RNF125, a gene that encodes for an E3 2 | MATERIAL AND METHODS
ubiquitin ligase mainly involved in protein–protein binding pro-
cesses that regulate protein expression and degradation through 2.1 | Patients
the proteasome system. Functional assays in patient-derived fibro-
blasts with RNF125 and its main target protein, RIG-1, suggested a All patients were recruited based upon the clinical defect in RNF125.
haploinsufficiency mechanism of RNF125 that might lead to the Patients were identified through the GeneMatcher platform (https://
dysregulation of the RIG1-IPS1-MDA5 pathway, which may also genematcher.org/). Informed consent and authorization for the
TENORIO-CASTAÑO ET AL. 3

publication of photographs were obtained by the referral centers. 3 | RE SU LT S


Clinical characterization was done at the referral centers where the
patients were followed up. The craniofacial phenotype of all available Networking scientific connections have allowed the identification of
patients is shown in Figure 1. This project was approved by the ethical fourteen additional individuals with pathogenic variants in RNF125,
committee of our Institution (CEIC-PI1543). Intellectual disability has and a presumptive clinical diagnosis of TNORS. Segregation analysis
been measured using tests and IQ calculations. Anxiety has been diag- showed that 53% of the probands inherited the variant from one of
nosed by a psychiatrist using clinical interviews and specific scales their parents, who were either asymptomatic or had mild forms of the
and tests (ISRA and similar). syndrome.
With the advances in massive paralleled sequencing technolo-
gies and by means of scientific network platforms such as
2.2 | Molecular analysis GeneMatcher,10 we have identified fourteen additional patients
with TNORS based on their molecular findings. Moreover, some of
All cases were analyzed by different NGS platforms including WES their clinical findings expand the phenotype of the syndrome and
and specific custom panels, covering the entire exons and intron-exon guide clinicians that not all the patients show overgrowth but the
boundaries of the RNF125 gene. Variants were classified according to most common findings are macrocephaly and a neu-
ACMG guidelines.9 rodevelopmental disorder (Table 2).

F I G U R E 1 Craniofacial phenotypes of patients with Tenorio syndrome. Patient 17 (L-M) was included in the first publication in 2014 [Colour
figure can be viewed at wileyonlinelibrary.com]

F I G U R E 2 Protein domain organization of RNF125. This protein has three functional domains, RING, Zinc-finger and UIM. All variants
detected in the 15 individuals are represented in red–including the patient with entire gene deletion- and the lower panels shows the correlation
between exons of the gene and the protein sequence. All detected pathogenic variants falls within the zinc-finger region. Legend: 1- RNF125
(NM_017831.4):c.47C>G:p.Ser16Cys 2- RNF125(NM_017831.4):c.146G>C:p.Arg49Pro 3- RNF125(NM_017831.4):c.181A>T:p.Ile61Phe
4- RNF125(NM_017831.4):c.336G>A:p.Met112Ile; 5- RNF125(NM_017831.4):c.371A>G:p.Asp124Gly; 6- RNF125(NM_017831.4):c.472A>G:p.
Ile158Val; 7- RNF125(NM_017831.4):c.488C>T:p.Ser163Leu; 8- RNF125(NM_017831.4):c.520C>T:(p.Arg174Cys); 8- (RNF125(NM_017831.4))
x1 [Colour figure can be viewed at wileyonlinelibrary.com]
4

T A B L E 1 Pathogenicity in silico analysis of RNF125 variants. All variants are absent or with extremely low frequency in the pseudocontrol databases. A specific database for pseudocontrols in
Spanish population have been also added. Pathogenicity prediction was applied by many in silico predictors from the dbNSFP. Classification of the pathogenicity of the variants was done according
the ACMG guidelines described in Richards et al.9 Genomic coordinates were annotated according to human genome reference hg19

RNF125 RNF125 RNF125 RNF125 RNF125 RNF125


RNF125 (NM_017831.4): (NM_017831.4): (NM_017831.4): (NM_017831.4): (NM_017831.4): (NM_017831.4):
Variant (cDNA (NM_017831.4): c.146G > C:p. c.181A > T:p. c.336G > A:p. c.371A > G:p. c.472A > G:p. c.488C > T:p. RNF125(NM_017831.4):
and protein) c.47C > G:p. Ser16Cys Arg49Pro Ile61Phe Met112Ile Asp124Gly Ile158Val Ser163Leu c.520C > T:p.Arg174Cys
Genomic
Coordinate
(hg19) chr18:29598873C > G chr18:29598972G > C chr18:29617095A > T chr18:29622159G > A chr18:29622194A > G chr18:29625663A > G chr18:29625679C > T chr18:29645880C > T
Mutation type missense missense missense missense missense missense missense missense

1000 Genomes 0 0 0 0 0 0 0/1000 0/1000


Database
Spanish N/A N/A N/A 0 0 0 0/600 0/600
population
(300 patients;
600
chromosomes)
Spanish Exomes N/A N/A N/A 0 0 0 0/350 0/350
(BIER)
(n = 350)
gnomAD 0.0000383 0 0 0 0 0 0.0000398 0.0000199
exomes (ExAc)
gnomAD 0.0000318 0 0 0 0 0 0 0
genomes
Beacon network 0 0 0 0 0 0 0 0
Bravo 0 0 0 0 0 0 0 0
Pathogenicity 3/21 11/21 13/21 15/21 7/21 1/21 12/21 7/21
toolsa
ACMG VUS Likely pathogenic Likely pathogenic Pathogenic Likely pathogenic Likely pathogenic Likely pathogenic Likely pathogenic
classification
Reference This study This study This study 2 This study This study 2 2
a
Pathogenicity tools: BayesDel addAF, BayesDel noAF, DANN, EIGEN, EIGEN PC, FATHMM, FATHMM-MKL, LRT, MVP, MetaLR, MetaSVM, MutPred, MutationTaster, PROVEAN, REVEL, SIFT4G, DEOGEN2, FATHMM-XF,
LIST-S2, Mutation assessor, PrimateAI, SIFT. The equation represented in the rows of 1000 Genomes Database, Spanish population (300 patients; 600 chromosomes), Spanish Exomes (BIER) (n = 350), represent the number
of individuals identified with the same variant as any of those detected in the patients described to date, with respect to the total number of individuals included in that database. In addition, the value of the pathogenicity
tools row represents the number of in silico bioinformatic predictors that predict a harmful effect of the variant, with respect to the total number of predictors consulted and mentioned above.
TENORIO-CASTAÑO ET AL.
TENORIO-CASTAÑO ET AL. 5

T A B L E 2 Clinical features in Tenorio syndrome. Percentage of the behavioral problems (anxiety), clumsiness, speech delay (sometimes
clinical features identified in the 20 patients described so far severe), macrocephaly and facial dysmorphic features including large
HPO Trait % n forehead, thick eyebrows, wide nose and macroglossia (Figure 1).

VERY FREQUENT (≥75%) Most patients identified in the present study had the same patho-
genic variants that were identified by us in 2014: p.Met112Ile (x3), p.
HP:0000256 Macrocephaly 85% 17/20
Asp124Gly (x3), p.Ile158Val (x2), p.Arg174Cys (x5) (Figure 2),
FREQUENT (50–74%)
suggesting that these are common changes in the disorder (Table 1).
HP:0001263 Developmental delay 60% 12/20
Analysis of the genetic variants revealed that some missense vari-
HP:0002003 Large forehead 60% 12/20
ants, were shared by several unrelated patients. The majority of the
HP:0001249 Intellectual disability 55% 11/20
detected/identified variants fall within or between the zinc-finger
HP:0000750 Speech delay/problems 50% 10/20
domains (C2H2, C2HC) although three variants were located outside
INFREQUENT (26–49%) this region, two within the RING domain p.(Arg49Pro) and p(Ile61Phe)
HP:0000445 Wide nose 45% 9/20 and one in the interdomain region p(Ser16Cys). Molecular analysis of
HP:0000708 Behavioral issues 45% 9/20 the variants is presented in Table 1. None of the variants have been
HP:0001548 Overgrowth 45% 9/20 previously reported in control population databases (>200 000
HP:0000574 Thick eyebrow 40% 8/20 pseudocontrol individuals) (gnomAD, Kaviar, Beacon, 1000G, ESP and
HP:0000739 Anxiety 35% 7/20 Bravo), the majority of the in silico pathogenicity-prediction tools

HP:0002312 Clumsiness 35% 7/20 suggested a damaging effect of all variants. Moreover, based on our
previous functional assays, some variants have been shown to disturb
HP:0000158 Macroglossia 30% 6/20
the function of RNF125.
HP:0002342 Intellectual disability, moderate 30% 6/20
RARE (≤25%)
HP:0001256 Intellectual disability, mild 25% 5/20
4 | DI SCU SSION
HP:0011968 Feeding or other issues 25% 5/20
HP:0000998 Hypertrichosis 25% 5/20
TNORS was first described in 2014 by Tenorio et al.2 The main clinical
HP:0000506 Telecanthus 20% 4/20 findings included overgrowth (mainly characterized by a macrocephaly
HP:0002090 Pneumonia 20% 4/20 and enlarged ventricles), autoimmune disorders resembling Sjögren
HP:0000717 Autism 15% 3/20 disease and/or Raynaud phenomenon, intellectual disability of vari-
HP:0001943 Hypoglycemia 15% 3/20 able degree, behavioral problems, speech delay, and craniofacial dys-
HP:0030880 Raynaud phenomenon 15% 3/20 morphic features such as large forehead, macroglossia, thick
HP:0002104 Apnea 15% 3/20 eyebrows and a wide nose. Since the description of the initial series

HP:0000491 Keratitis 15% 3/20 of patients in 2014, no additional cases have been published.
In this article, we report fourteen new patients with TNORS, and
HP:0001250 Seizures 10% 2/20
include a full overall review of the clinical and molecular findings
HP:0002389 Cavum septum pellucidum 10% 2/20
(Supplementary Table S1) of the total of eighteen cases.
HP:0000509 Conjunctivitis 10% 2/20
Macrocephaly was the most common feature, as it has been observed
HP:0002020 Gastroesophageal reflux 10% 2/20
in 89% of individuals, with some of them manifesting hydrocephaly.
HP:0000388 Otitis media 10% 2/20
Clinical features counting more than 50% of patients were: at neuro-
HP:0000938 Osteopenia 10% 2/20
logical level, developmental delay (60%), intellectual disability (55%),
HP:0010280 Stomatitis 10% 2/20 speech delay/problems (50%) and craniofacial dysmorphic features
HP:0011107 Recurrent aphthous stomatitis 10% 2/20 such as large forehead (60%). Less frequent clinical characteristics
HP:0001096 Keratoconjunctivitis 10% 2/20 were: mild to moderate intellectual disability, some behavioral
HP:0100021 Cerebral palsy 5% 1/20 problems including anxiety and psychotic episodes, speech delay/
HP:0001528 Hemihypertrophy 5% 1/20 problems, clumsiness, macroglossia, thick eyebrows and wide nose
HP:0002650 Scoliosis 5% 1/20 (Table 2).

HP:0001279 Syncope 5% 1/20 TNORS can be classified as a neurodevelopmental disorder that


may include overgrowth (mainly macrocephaly). Patients with OGS
HP:0040216 Hypoinsulinemia 5% 1/20
such as Sotos, Malan, Weaver and Beckwith-Wiedemann syndrome
Abbreviations: N, number of individuals with the specific feature among all
show distinctive craniofacial features that may help to distinguish with
described; N/A: not applicable.
TNORS. For instance, some patients who had macroglossia and large
Clinical deep phenotyping and a review of the novel and publi- forehead were initially diagnosed with Beckwith-Wiedemann or
shed individuals revealed that the most common findings among all Simpson-Golabi-Behmel syndrome. Differential diagnosis should also
patients were: mild to moderate neurodevelopmental delay, include: Sotos syndrome, Weaver syndrome, Tatton-Brown-Rahman
6 TENORIO-CASTAÑO ET AL.

syndrome due to pathogenic variants in DNMT3A,11 and intellectual between variants in ring-finger proteins and neurodevelopmental
disability due to pathogenic variants in BRWD3.12 disorders.
RNF125 encodes for an E3 ubiquitin ligase protein, which is involved Segregation analyses showed that most patients inherited the
mainly in a redundant process of binding proteins and adding lysine resi- variant from one of their parents. In fact, approximately half of
dues to facilitate the degradation of those proteins through the the patients with pathogenic or probably pathogenic variants in
proteasome. Other genes that encode for E3 ubiquitin and ligases and RNF125 such variant was also present in one of their parents.
related to head size anomalies have been previously described by us and Although in the initial examination of the transmitting parents showed
by other groups.13,14 RNF125 has been also involved in the innate no apparent clinical manifestations of the syndrome, deep
immune response by the action of either RIG-I or MDA5, depending on phenotyping and cognitive screening revealed that some of them had
the activation pathway. In fact, RIG-1 has been found to be related to borderline or mild intellectual disability, while others (e.g., mother of
the PI3K-AKT pathway in which many of its genes have already been P5 in this report, P6 in the original paper from Tenorio et al.) showed
associated not only with overgrowth but also with neurodevelopmental some clinical features as well. Thus, confirmation of segregation is
disorders. Therefore, RNF125 might have an indirect effect on this extremely important and, therefore, always recommended to identify
molecular pathway. Moreover, recent studies have also associated relatives with milder forms of the syndrome, to whom it can be
RNF125 expression with the more aggressive forms of gallbladder can- offered a proper management and a precise genetic counseling. Due
cer because it activates the TGF-β1-SMAD3-ID1 signaling pathway.15 to the overlap of TNORS with other overgrowth and neu-
Functional studies of RNF125, reported in our first paper demon- rodevelopmental disorders, molecular diagnosis must be carried out
strated that the pathogenic variants identified prevented the degrada- using massive parallel sequencing techniques, specifically whole
tion of RIG1 and, therefore, that this protein might accumulate in the exome sequencing (WES).
cytoplasm, potentially overactivating some downstream pathways. Thus, it is clear that the phenotype of TNORS is highly heteroge-
Based on the findings mentioned above, haploinsufficiency is the neous; ranging from patients with subtle or mild neuropsychological
most likely mechanism associated with the development of TNORS. manifestations (mild forms) to individuals with moderate/severe
Further experiments are necessary to explore the possible role of manifestations. This is especially important for genetic counseling of
RIG-I in the PI3K-AKT pathway, and how this might contribute to the families where only one member has been diagnosed with TNORS. In
phenotype development associated with TNORS. fact, we have found behavioral disturbances in three patients. Patient
We found eight pathogenic missense variants and one entire five suffered from severe postpartum depression with psychotic
deletion of the gene in 20 individuals, most of them located in the behavior, patient eight had severe behavior disturbances, including
zinc-finger domains or in the regions linking these domains (Figure 2). suicidal tendencies, refractory to pharmacological treatment, and
Only two of the variants falls within the RING domain of the protein. finally, patient 14 suffered several years from severe depression,
The zinc/ring finger domains are present mainly in proteins whose obsessions and anxiety that required multi-drug treatment.
functions include ubiquitination. They are domains that have a Cys(n) Interestingly, patient seven had additional findings including eye
HisCys(n) type structure and that have the ability to bind to some sub- anomalies (strabismus and mild enophthalmia), floppy ears, tapered
strates and/or enzymes in order to be degraded in the proteasome hands, Meckel diverticulum, biliary lithiasis that required cholecystec-
and thus regulating their expression. tomy, and subcortical–cortical atrophy and small corpus callosum. He
In that sense, given that most of the variants that have been iden- had, besides the variant in RNF125, a likely pathogenic heterozygous
tified in TNORS are missense, it is possible that they are preventing variant in MED13L (p.Gln689*),20 which could explain, at least in part,
allosteric regulation, and therefore, binding to the proteins on which his complex phenotype (Table SS1).
RNF125 acts, mainly RIG-I and MDA5. In turn, these two proteins In summary, we present fourteen additional patients with TNORS
accumulate in the cytoplasm and can overexpress their function on and review the clinical and molecular findings of the total 20 patients
some pathways such as the PI3K-AKT pathway, of which we know reported here, highlighting the wide heterogeneity of the syndrome
that there are already other genes of the same pathway with gain-of- even among members of the same family. The main clinical findings
function mutations associated with the development of some patholo- are the presence of a neurodevelopmental disorder with craniofacial
gies (i.e., GOF pathogenic variants in MTOR associated with Smith- dysmorphic features, especially macrocephaly with large forehead, in
Kingsmore syndrome). the majority of the patients. At the molecular level, we have demon-
Other ring finger proteins belonging to the same family have been strated that most pathogenic variants cluster in a region of RNF125,
associated with neurodevelopmental disorders: RLIM in X-linked with the majority located within the zinc-finger domain of the protein.
16
Tonne-Kalscheuer syndrome (MIM #300978), RNF216- in Gordon- Further studies are needed to elucidate the specific mechanism by
Holmes syndrome (also known as Cerebellar Ataxia and which the haploinsufficiency of RNF125 leads to the development of
Hypogonadotropic Hypogonadism; MIM #212840),17 homozygous TNORS.
pathogenic variants in RNF268 in RIDDLE syndrome (MIM
#611943)18 and heterozygous pathogenic variants in RNF13 in Devel- ACKNOWLEDG MENTS
opmental and Epileptic Encephalopathy 73 (MIM #618379), among The authors would like to thank all the families and patients for
others.19 This information adds further evidence of the relationship accepting to participate in this study. the authors also thank the
TENORIO-CASTAÑO ET AL. 7

Spanish Overgrowth Registry Consortium (SOGRI) and all clinicians 9. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the
who have participated in this work. This study was funded by Federa- interpretation of sequence variants: a joint consensus recommenda-
tion of the American College of Medical Genetics and Genomics and
 n Española de Enfermedades Raras (FEDER) funds ISCIII, PI20/
cio
the Association for Molecular Pathology. Genet Med. 2015;17:
01053. 405-424.
10. Sobreira N, Schiettecatte F, Valle D, Hamosh A. GeneMatcher: a
CONF LICT OF IN TE RE ST matching tool for connecting investigators with an interest in the
same gene. Hum Mutat. 2015;36:928-930.
Authors declared no conflict of interest.
11. Tenorio J, Alarcon P, Arias P, et al. Further delineation of neuropsy-
chiatric findings in Tatton-Brown-Rahman syndrome due to disease-
AUTHOR CONTRIBUTION causing variants in DNMT3A: seven new patients. Eur J Human Genet.
JAT and PL designed the work and wrote the manuscript. PA per- 2020;28:469-479.
12. Tenorio J, Alarcon P, Arias P, et al. MRX93 syndrome (BRWD3 gene):
formed all the sequencing techniques, NG, SR and JT, SA performed
five new patients with novel mutations. Clin Genet. 2019;95:726-731.
the molecular analyses, AFJ, GL, AB, LOF, JL, FTM, FSS, LP, FMM, 13. Nevado J, Rosenfeld JA, Mena R, et al. PIAS4 is associated with
GBL, FJR, and MMO identified additional patients and recorded clini- macro/microcephaly in the novel interstitial 19p13.3 micro-
cal and molecular data. deletion/microduplication syndrome. Eur J Human Genet. 2015;23:
1615-1626.
14. Tenorio J, Nevado J, Gonzalez-Meneses A, et al. Further definition of
P EE R R EV I E W
the proximal 19p13.3 microdeletion/microduplication syndrome and
The peer review history for this article is available at https://publons. implication of PIAS4 as the major contributor. Clin Genet. 2020;97:
com/publon/10.1111/cge.14020. 467-476.
15. Liu ZY, Cao J, Zhang JT, et al. Ring finger protein 125, as a potential
highly aggressive and unfavorable prognostic biomarker, promotes
DATA AVAI LAB ILITY S TATEMENT
the invasion and metastasis of human gallbladder cancers via activat-
Data sharing is not applicable to this article as no new data were cre- ing the TGF- beta1-SMAD3-ID1 signaling pathway. Oncotarget.
ated or analyzed in this study. 2017;8:49897-49914.
16. Frints SGM, Ozanturk A, Rodriguez Criado G, et al. Pathogenic vari-
ants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked
ORCID
intellectual disability and behavior disorder. Mol Psychiatry. 2019;24:
Antonio Federico Martínez-Monseny https://orcid.org/0000-0002- 1748-1768.
0960-3153 17. Santens P, Van Damme T, Steyaert W, et al. RNF216 mutations as a
Elliot S. Stolerman https://orcid.org/0000-0001-9536-4621 novel cause of autosomal recessive Huntington-like disorder. Neurol-
ogy. 2015;84:1760-1766.
18. Stewart GS, Panier S, Townsend K, et al. The RIDDLE syndrome pro-
RE FE R ENC E S tein mediates a ubiquitin-dependent signaling cascade at sites of
1. Lapunzina P. Risk of tumorigenesis in overgrowth syndromes: a com- DNA damage. Cell. 2009;136:420-434.
prehensive review. Am J Med Genet C Semin Med Genet. 2005;137C: 19. Edvardson S, Nicolae CM, Noh GJ, et al. Heterozygous RNF13 gain-
53-71. of-function variants are associated with congenital microcephaly, epi-
2. Tenorio J, Mansilla A, Valencia M, et al. A new overgrowth syndrome leptic encephalopathy, blindness, and failure to thrive. Am J Hum
is due to mutations in RNF125. Hum Mutat. 2014;35:1436-1441. Genet. 2019;104:179-185.
3. Biesecker LG, Sapp JC. Proteus Syndrome. In: Adam MP, 20. Smol T, Petit F, Piton A, et al. MED13L-related intellectual disability:
Ardinger HH, Pagon RA, et al., eds. GeneReviews([R]). Seattle (WA); involvement of missense variants and delineation of the phenotype.
1993. Neurogenetics. 2018;19:93-103.
4. Keppler-Noreuil KM, Rios JJ, Parker VE, et al. PIK3CA-related over-
growth spectrum (PROS): diagnostic and testing eligibility criteria, dif-
ferential diagnosis, and evaluation. Am J Med Genet A. 2015;167A: SUPPORTING INF ORMATION
287-295.
Additional supporting information may be found online in the
5. Gordo G, Tenorio J, Arias P, et al. mTOR mutations in smith-
Kingsmore syndrome: four additional patients and a review. Clin
Supporting Information section at the end of this article.
Genet. 2018;93:762-775.
6. Rademacher S, Eickholt BJ. PTEN in autism and neurodevelopmental
disorders. Cold Spring Harb Perspect Med. 2019;9:a036780. How to cite this article: Tenorio-Castaño JA, Arias P,
7. Chen J, Alberts I, Li X. Dysregulation of the IGF-I/PI3K/AKT/mTOR Fernandez-Jaén A, et al. Tenorio syndrome: Description of 14
signaling pathway in autism spectrum disorders. Int J Dev Neurosci. novel cases and review of the clinical and molecular features.
2014;35:35-41.
Clinical Genetics. 2021;1-7. https://doi.org/10.1111/cge.
8. Borrie SC, Brems H, Legius E, Bagni C. Cognitive dysfunctions in intel-
lectual disabilities: the contributions of the Ras-MAPK and PI3K-AKT- 14020
mTOR pathways. Annu Rev Genomics Hum Genet. 2017;18:115-142.